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* Institute of Pathophysiology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria;
Atomic Energy Commission (CEA), Institut de Biologie et Technologies de Saclay (iBiTecS), Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), Gif-sur-Yvette, France;
Institute of Immunology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna,
Christian Doppler Laboratory for Immunomodulation, and
¶ Department of Blood Group Serology, Medical University of Vienna, Vienna, Austria;
|| Christian Doppler Laboratory for Allergy Diagnosis and Therapy, University of Salzburg, Salzburg, Austria; and
# Allergieambulatorium Reumannplatz, Vienna, Austria
More than 95% of mugwort pollen-allergic individuals are sensitized to Art v 1, the major allergen in mugwort pollen. Interestingly, the CD4 T cell response to Art v 1 involves only one single immunodominant peptide, Art v 125–36 (KCIEWEKAQHGA), and is highly associated with the expression of HLA-DR1. Therefore, we investigated the molecular basis of this unusual immunodominance among allergens. Using artificial APC expressing exclusively HLA-DRB1*0101 and HLA-DRA*0101, we formally showed that DR1 acts as restriction element for Art v 125–36-specific T cell responses. Further assessment of binding of Art v 125–36 to artificial HLA-DR molecules revealed that its affinity was high for HLA-DR1. Amino acid I27 was identified as anchor residue interacting with DR molecules in pocket P1. Additionally, Art v 125–36 bound with high affinity to HLA-DRB1*0301 and *0401, moderately to HLA-DRB1*1301 and HLA-DRB5*0101, and weakly to HLA-DRB1*1101 and *1501. T cell activation was also inducible by Art v 125–36-loaded, APC-expressing HLA molecules other than DR1, indicating degeneracy of peptide binding and promiscuity of TCR recognition. Specific binding of HLA-DRB1*0101 tetramers containing Art v 119–36 allowed the identification of Art v 125–36-specific T cells by flow cytometry. In summary, the immunodominance of Art v 125–36 relies on its affinity to DR1, but is not dictated by it. Future investigations at the molecular HLA/peptide/TCR and cellular level using mugwort pollen allergy as a disease model may allow new insights into tolerance and pathomechanisms operative in type I allergy, which may instigate new, T cell-directed strategies in specific immunotherapy.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the Austrian Research Foundation (P20011-B09, P-15634, SFB-F1807, SFB-F1816) and Biomay, Vienna, Austria.
2 Address correspondence and reprint requests to Dr. Beatrice Jahn-Schmid, Department of Pathophysiology, Center of Physiology, Pathophysiology and Immunology, Medical University of Vienna, Währinger Gürtel 18-20, AKH-3Q, A-1090 Wien, Austria. E-mail address: beatrice.jahn-schmid{at}meduniwien.ac.at
3 Abbreviations used in this paper: n, natural; Ii, invariant chain; r, recombinant; SI, stimulation index; TCC, T cell clone; TCL, T cell line.
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